Several substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are known gastric proton pump inhibitors; and these include omeprazole, lansoprazole, pantoprazole, and rabeprazole. Lansoprazole is a reversible proton (acid) pump inhibitor. Lansoprazole per se is protected by U.S. Pat. No. 4,628,098 owned by Takeda. Lansoprazole is chemically known as (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole) and has the following chemical formula A:
wherein R1 is methyl, R2 is trifluoro-ethoxy, and R3 is hydrogen and R4 is hydrogen. Other benzimidazole derivatives (e.g., omeprazole and pantoprazole) share the ability of lansoprazole to inhibit gastric acid secretion, and these compounds are commonly recognized as anti-ulcer agents.
The preparation of lansoprazole by conventional methods is generally accompanied by the formation of small quantities of the corresponding sulfone derivative as an impurity. For example, U.S. Pat. No. 6,180,652 describes the presence of sulfone derivative. Formation of sulfone derivative brings about the drawback of low yield of the desired sulfoxide. U.S. Pat. No. 6,180,652 describes a method that permits separation of lansprazole from its sulfone derivative and discloses an acetone complex of the lansoprazole salt.
Lansoprazole and other 2-(2-pyridylmethyl)sulfinyl-benzimidazole derivatives tend to lose stability and undergo decomposition when contaminated with traces of a solvent, particularly water, in its crystal structure. It is desirable that the benzimidazole crystals be solvent free (i.e., residual solvent should be reduced to a minimum).
Lansoprazole is a relatively unstable compound, especially in acidic conditions, but also under strongly basic conditions. U.S. Pat. No. 6,002,011 (“the '011 patent”) discloses that lansoprazole is unstable under usual storage conditions. The '011 patent discloses a reslurry method in water which permits the preparation of ‘solvent-free lansoprazole’ which, according to the '011 patent, demonstrates improved stability. By ‘solvent-free lansoprazole’, the '011 patent specifically defines a lansoprazole product containing not more than about 500 ppm water and not more than about 200 ppm alcohol.
Both the '011 patent and U.S. Pat. No. 5,578,732 describes the crystallization of lansoprazole using an ethanol:water solvent system (vol:vol of ethanol:water is 9:1). The '011 patent further describes that this ethanol:water crystallization system has a limited purification effect even if traces of ammonium hydroxide (0.03 M NH4OH: 1M lansoprazole) is used. The '011 patent fails to disclose a purity level for lansoprazole. The '011 patent describes an ethanolate solvate form and an ethanolate-hydrate form of lansoprazole. The '011 patent specifically discloses that a lansoprazole, when containing ≧500 ppm water or ≧200 ppm ethanol, is unstable and therefore unsuitable to be a pharmaceutical composition. Inasmuch as the ethanol and water are difficult to eliminate, benzimidazole derivative compounds prepared by this crystallization process still contain solvent even after intensive drying. Consequently, such lansoprazole is unstable under storage.
In “Stabilization of a New Anti-ulcer Drug (Lansoprazole) in the Solid Dosage Forms,” by Tabata et al., Drug Development and Industrial Pharmacy, 18(13) 1437-47 (1992), the mechanism of stabilization of lansoprazole in enteric granules is discussed. The publication discloses that lansoprazole is unstable under conditions of high temperature and also high humidity, with a decrease in the amount of lansoprazole and discoloration of the material being noted on storage under such conditions. The variation in assay and color of solid lansoprazole over time on storage at various temperatures and humidities is presented in Table 2, at page 1439. The table shows that after 4 months at 40° C. and 75% room humidity lansoprazole turns pale brown, and even in the absence of humidity under the same conditions, lansoprazole turns pale yellowish brown. The publication explains the unusually high instability of lansoprazole under even weak acidic conditions as being due to proton attack on the sulfoxide group. Lansoprazole seems to be especially sensitive to such attack compared to the other members of the 2-(2-pyridylmethyl)sulfinyl-benzimidazole family of drugs.
The article further discloses that degradation of lansoprazole is minimized under weakly basic conditions, and concludes that the degradation of lansoprazole in dosage forms is minimized by the formulated to also contain stabilizing compounds suitable to produce such a weakly basic pH. The article, however, does not address the use of lansoprazole as an active pharmaceutical ingredient. As such, lansoprazole must be stored and transported, often for long time periods, and therefore the need exists for a stable form of lansoprazole which does not suffer degradation and/or discoloration even if stored or transported under non-optimum conditions. The present invention provides such a stable lansoprazole and a method for its production.